Conformationally constrained peptide analogues of pTyr-Glu-Glu-Ile as inhibitors of the src SH2 domain binding

被引：55

作者：

Nam, NH

Ye, GF

Sun, GQ

Parang, K ^{[1
]}

机构：

[1] Univ Rhode Isl, Dept Biomed Sci, Kingston, RI 02881 USA

[2] Univ Rhode Isl, Dept Cell & Mol Biol, Kingston, RI 02881 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 12期

关键词：

D O I：

10.1021/jm040008+

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of conformationally constrained peptides were designed and synthesized as the Src SH2 domain ligands based on a tetrapeptide sequence pTyr-Glu-Glu-Ile (pYEEI). In general, the constrained peptides such as compounds 6, 7, and 11 (IC50 = 1.1-1.5 muM) showed higher binding affinities to the Src SH2 domain relative to the corresponding linear peptides 8a, 9a, and 13a, respectively (IC50 > 100 muM), and pYEEI (IC50 = 6.5 muM), as evaluated by a fluorescence polarization assay. Molecular modeling studies revealed that in constrained peptides, the isoleucine side chain penetrates very deeply into the hydrophobic binding pocket (P + 3 site) of the Src SH2 domain. These constrained peptides can serve as novel templates for the design of small and nonpeptidic inhibitors of the Src SH2 domain.

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收藏

页码：3131 / 3141

页数：11

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[21] Use of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide mimics in SH2 antagonists [J].

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PANT, N ;

COWBURN, D ;

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[29] Structure-based design of novel bicyclic nonpeptide inhibitors for the Src SH2 domain [J].

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Lu, XD ;

Violette, SM ;

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